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Pharmacological Challenge (pharmacological + challenge)

Distribution by Scientific Domains
Medical Sciences60%
Life Sciences40%

Selected Abstracts

ANALYSIS OF SHORT-TERM REPRODUCIBILITY OF ARTERIAL VASOREACTIVITY BY PULSE-WAVE ANALYSIS AFTER PHARMACOLOGICAL CHALLENGE

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1 2009
Biju Paul
SUMMARY 1Pulse-wave analysis (PWA) is an established method to assess arterial wave reflections and arterial vasoreactivity in humans. A high short-term reproducibility of baseline augmentation index (AIx) has been reported. However, the short-term reproducibility of AIx changes following pharmacological challenge with either inhaled salbutamol (endothelium-dependent vasodilatation) or sublingual glyceryl trinitrate (GTN; endothelium-independent vasodilatation), using appropriate statistical methods, is largely unknown. 2Baseline AIx and GTN- and salbutamol-mediated changes in AIx (all corrected for a heart rate of 75 b.p.m.) were measured on two separate occasions, 1 h apart, in 22 healthy controls (mean (±SD) age 52.0 ± 13.4 years) and 11 elderly patients with chronic heart failure (CHF; 73.1 ± 8.7 years). Reproducibility was assessed by measuring intraclass correlation coefficients (ICC), coefficients of variation (CV) and Bland,Altman plots. 3Baseline AIx showed good short-term reproducibility with high ICC in both the control and CHF groups (0.90 and 0.87, respectively). In contrast, in the control and CHF groups, the ICC of GTN- (0.58 and 0.17, respectively) and salbutamol-mediated (0.18 and 0.04, respectively) changes in AIx were substantially low. The CV was relatively low for baseline AIx in control and CHF groups (25.0 and 22.5%, respectively), but not for GTN- (22.3 and 59.8%, respectively) or salbutamol-mediated (45.1 and 184.0%, respectively) changes in AIx. Bland,Altman analysis revealed poor reproducibility, with limits of agreement beyond either +15% or ,15% for changes in AIx after GTN and salbutamol for both control and CHF groups. The changes in blood pressure and heart rate following pharmacological challenge were similar between the two measurements. 4The poor reproducibility of changes in AIx following pharmacological challenge questions the use of this method in acute studies. [source]

Deficits in acetylcholine homeostasis, receptors and behaviors in choline transporter heterozygous mice

GENES, BRAIN AND BEHAVIOR, Issue 5 2007
M. H. Bazalakova
Cholinergic neurons elaborate a hemicholinium-3 (HC-3) sensitive choline transporter (CHT) that mediates presynaptic, high-affinity choline uptake (HACU) in support of acetylcholine (ACh) synthesis and release. Homozygous deletion of CHT (,/,) is lethal shortly after birth (Ferguson et al. 2004), consistent with CHT as an essential component of cholinergic signaling, but precluding functional analyses of CHT contributions in adult animals. In contrast, CHT+/, mice are viable, fertile and display normal levels of synaptosomal HACU, yet demonstrate reduced CHT protein and increased sensitivity to HC-3, suggestive of underlying cholinergic hypofunction. We find that CHT+/, mice are equivalent to CHT+/+ siblings on measures of motor co-ordination (rotarod), general activity (open field), anxiety (elevated plus maze, light/dark paradigms) and spatial learning and memory (Morris water maze). However, CHT+/, mice display impaired performance as a result of physical challenge in the treadmill paradigm, as well as reduced sensitivity to challenge with the muscarinic receptor antagonist scopolamine in the open field paradigm. These behavioral alterations are accompanied by significantly reduced brain ACh levels, elevated choline levels and brain region-specific decreased expression of M1 and M2 muscarinic acetylcholine receptors. Our studies suggest that CHT hemizygosity results in adequate baseline ACh stores, sufficient to sustain many phenotypes, but normal sensitivities to physical and/or pharmacological challenge require full cholinergic signaling capacity. [source]

ANALYSIS OF SHORT-TERM REPRODUCIBILITY OF ARTERIAL VASOREACTIVITY BY PULSE-WAVE ANALYSIS AFTER PHARMACOLOGICAL CHALLENGE

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1 2009
Biju Paul
SUMMARY 1Pulse-wave analysis (PWA) is an established method to assess arterial wave reflections and arterial vasoreactivity in humans. A high short-term reproducibility of baseline augmentation index (AIx) has been reported. However, the short-term reproducibility of AIx changes following pharmacological challenge with either inhaled salbutamol (endothelium-dependent vasodilatation) or sublingual glyceryl trinitrate (GTN; endothelium-independent vasodilatation), using appropriate statistical methods, is largely unknown. 2Baseline AIx and GTN- and salbutamol-mediated changes in AIx (all corrected for a heart rate of 75 b.p.m.) were measured on two separate occasions, 1 h apart, in 22 healthy controls (mean (±SD) age 52.0 ± 13.4 years) and 11 elderly patients with chronic heart failure (CHF; 73.1 ± 8.7 years). Reproducibility was assessed by measuring intraclass correlation coefficients (ICC), coefficients of variation (CV) and Bland,Altman plots. 3Baseline AIx showed good short-term reproducibility with high ICC in both the control and CHF groups (0.90 and 0.87, respectively). In contrast, in the control and CHF groups, the ICC of GTN- (0.58 and 0.17, respectively) and salbutamol-mediated (0.18 and 0.04, respectively) changes in AIx were substantially low. The CV was relatively low for baseline AIx in control and CHF groups (25.0 and 22.5%, respectively), but not for GTN- (22.3 and 59.8%, respectively) or salbutamol-mediated (45.1 and 184.0%, respectively) changes in AIx. Bland,Altman analysis revealed poor reproducibility, with limits of agreement beyond either +15% or ,15% for changes in AIx after GTN and salbutamol for both control and CHF groups. The changes in blood pressure and heart rate following pharmacological challenge were similar between the two measurements. 4The poor reproducibility of changes in AIx following pharmacological challenge questions the use of this method in acute studies. [source]

5-HT1B receptor knockout mice show a compensatory reduction in 5-HT2C receptor function

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2003
Peter G. Clifton
Abstract Although null mutant (,knockout') mice have provided valuable animal models to complement traditional approaches to psychopharmacology, such animals may also show complex adaptations to the induced mutation. Here we demonstrate that serotonin1B (5-HT1B) receptor knockout (KO) mice show adaptations in serotonin2C (5-HT2C) receptor-mediated functions. They show smaller reductions in food intake and locomotor activity in response to administration of 5-HT2C receptor agonists that are not accounted for by altered drug disposition. These effects are not mimicked by pretreatment of wildtype (WT) mice with a 5-HT1B receptor antagonist showing that they result from a longer term adaptation to the loss of 5-HT1B receptor function and not from a short-term interaction between 5-HT1B - and 5-HT2C -mediated functions. In addition, we show that 5-HT1B receptor KO mice have a lowered hypothalamic c-fos response to the administration of 5-HT2C receptor agonists. These results demonstrate that compensatory adaptations to the constitutive loss of 5-HT1B receptors may be an important determinant of the altered response of 5-HT1B KO mice to a variety of pharmacological challenges. [source]

Fibrinolysis, inflammation, and regulation of the plasminogen activating system

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 2007
R. L. MEDCALF
Summary., The maintenance of a given physiological process demands a coordinated and spatially regulated pattern of gene regulation. This applies to genes encoding components of enzyme cascades, including those of the plasminogen activating system. This family of proteases is vital to fibrinolysis and dysregulation of the expression pattern of one or more of these proteins in response to inflammatory events can impact on hemostasis. Gene regulation occurs on many levels, and it is apparent that the genes encoding the plasminogen activator (fibrinolytic) proteins are subject to both direct transcriptional control and significant post-transcriptional mechanisms. It is now clear that perturbation of these genes at either of these levels can dramatically alter expression levels and have a direct impact on the host's response to a variety of physiological and pharmacological challenges. Inflammatory processes are well known to impact on the fibrinolytic system and to promote thrombosis, cancer and diabetes. This review discusses how inflammatory and other signals affect the transcriptional and post-transcriptional expression patterns of this system, and how this modulates fibrinolysis in vivo. [source]